Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that functions by limiting cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR2## wherein: R.sup.3 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R.sup.* is ##STR3## wherein N is ##STR4## R.sup.5 is H or OH; M is ##STR5## R.sup.6 is hydrogen or hydroxy; R.sup.2 is hydrogen or methyl; and a, b, c, and d represent single bonds, one of a, b, c or d represents a double bond, or both a and c or both b and d represent double bonds provided that when a is a double bond, N is ##STR6## and when d is a double bond, M is ##STR7## PA1 Q is CH.sub.3, CH.sub.2 OT, or H; PA1 T is H, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl or tetrahydropyranyl; PA1 Z is OCH.sub.3, or Z together with the carbon to which it is attached represents C.dbd.O; PA1 R.sub.1 is selected from: PA1 R.sub.N is selected from: PA1 X and Y independently are hydrogen, halogen, trifluoromethyl, C.sub.1-3 alkyl, nitro, cyano or a group selected from: PA1 Q is CH.sub.3, CH.sub.2 OT, or H; PA1 T is H, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl or tetrahydropyranyl; PA1 Z is OCH.sub.3, or Z together with the carbon to which it is attached represents C.dbd.O; PA1 R.sub.1 is selected from: PA1 X and Y independently are hydrogen, halogen, trifluoromethyl, C.sub.1-3 alkyl, nitro, cyano or group selected from: PA1 (1) C.sub.1-10 alkyl; PA1 (2) substituted C.sub.1-10 alkyl in which one or more substituent(s) is selected from PA1 (3) C.sub.3-8 cycloalkyl; PA1 (4) substituted C.sub.3-8 cycloalkyl in which one substituent is selected from PA1 (5) phenylamino; PA1 (6) substituted phenylamino in which the substituents are X and Y; PA1 (7) phenyl C.sub.1-10 alkylamino; and PA1 (8) substituted phenyl C.sub.1-10 alkylamino in which the substituents are X and Y. PA1 R.sub.1 is selected from: PA1 R.sub.1 is C.sub.1-10 alkyl; PA1 Q is CH.sub.3 ; and PA1 a is a single bond. PA1 T is tert-butyldimethylsilyl; PA1 R.sub.1 is 2-methyl-2-butyl or 2-butyl. PA1 (1) R.sub.1 is 2-methyl-2-butyl, A is OH, Z is C.dbd.O; PA1 (2) R.sub.1 is 2-butyl, A is OH, Z is C.dbd.O; PA1 (3) R.sub.1 is 2-methyl-2-butyl, A is SH, Z is OCH.sub.3 ; PA1 (4) R.sub.1 is 2-butyl, A is SH, Z is OCH.sub.3. PA1 Q is CH.sub.3, CH.sub.2 OT, or H; PA1 T is H, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl or tetrahydropyranyl; PA1 Z together with the carbon to which it is attached is C.dbd.O; PA1 R.sub.1 is selected from: PA1 R.sub.N is selected from: PA1 X and Y independently are hydrogen, halogen, trifluoromethyl, C.sub.1-3 alkyl, nitro, cyano or group selected from: PA1 (1) C.sub.1-10 alkyl; PA1 (2) substituted C.sub.1-10 alkyl in which one or more substituent(s) is selected from PA1 (3) C.sub.3-8 cycloalkyl; PA1 (4) substituted C.sub.3-8 cycloalkyl in which one substituent is selected from PA1 (5) phenylamino; PA1 (6) substituted phenylamino in which the substituents are X and Y; PA1 (7) phenyl C.sub.1-10 alkylamino; and PA1 (8) substituted phenyl C.sub.1-10 alkylamino in which the substituents are X and Y. PA1 R.sub.1 is selected from: PA1 R.sub.1 is C.sub.1-10 alkyl; PA1 Q is CH.sub.3 ; and PA1 a is a single bond. PA1 T is tert-butyldimethylsilyl; PA1 R.sub.1 is 2-methyl-2-butyl or 2-butyl. PA1 R.sub.N is phenylCH.sub.2 --. PA1 (1) R.sub.1 is 2-methyl-2-butyl; PA1 (2) R.sub.1 is 2-butyl. PA1 (i) Treating the compound (1--1) ##STR27## wherein R.sub.1, and Q are defined above, with a tris(triarylphosphine) rhodium halide in the presence of hydrogen to form a compound of formula (1-2); ##STR28## (ii) Treating compound (1-2) with ozone in an alcoholic solvent followed by reduction of the ozonide with zinc/acetic acid and reduction of the intermediate ketoaldehyde with sodium borohydride to yield compound (1-3); ##STR29## (iii) Contacting compound (1-3) with an iodinating reagent such as iodine/triphenylphosphine/imidazole to form compound (1-4); ##STR30## (iv) Treating compound (1-4) with a 2-nitrophenyl selenocyanate and NaBH.sub.4 to yield a compound (1-5); ##STR31## (v) Treating compound (1-5) with H.sub.2 O.sub.2 /THF to yield compound (1-6); ##STR32## PA1 (vi) Contacting compound (1-6) with diisobutylaluminum hydride (dibal) to yield compound (4-7); ##STR36## (vii) treating compound (4-7) with methanol and para-toluenesulfonic acid (pTSA) to yield compound (4-8); ##STR37## (viii) treating compound (4-8) with (COCl).sub.2 and dimethylsulfoxide (DMSO) and a base such as triethylamine to yield compound (4-9); ##STR38## (ix) treating compound (4-9) with a dehydrogenating agent such as PdCl.sub.2 /Pd(OAc).sub.2 to yield the eneone compound (4-10); ##STR39## (x) treating compound (4-10) with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide to yield the thione (4-11); ##STR40## (xi) treating compound (4-11) with a thione reducing agent such as NaBH.sub.4 to yield the intermediate (B) (4-12); ##STR41## PA1 (xii) treating compound (1-6) with (ClCO).sub.2 in DMSO and a base such as triethylamine to yield compound (5-7); ##STR42## (xiii) contacting compound (5-7) with R.sub.N NH.sub.2, an alkyl or arylalkylamine such as benzylamine and NaCNBH.sub.3 to yield an intermediate (B) (5-8); ##STR43## Intermediates of formula B wherein A is HNR.sub.N and a is a double bond are prepared in a sequence comprising steps (i).fwdarw.(v) and step (xii) as discussed above for scheme 5 and further comprising:
Copending patent application Ser. No. 212,767 filed June 29, 1988 discloses 6-substituted compounds of the above general formula wherein R.sup.* is ##STR8## wherein A is O, S(O).sub.n or N--R.sup.13.